Prevention trials for Alzheimer's disease (AD) require development of biological markers to identify normal (NL) individuals at increased risk for decline. After age, having a 1st degree family history (FH) of late-onset AD is the most significant risk factor for developing AD among NL, especially when a parent is affected. The biological mechanisms through which a parental FH of AD confers risk to the offspring are not known. Using Positron Emission Tomography imaging with 2-[18F]fluoro-2-Deoxy-D-glucose as the tracer (FDG-PET), we demonstrated that NL elderly with a maternal history of AD (FHm) show reductions in the cerebral metabolic rate of glucose (CMRglc) as compared to those with a paternal history of AD (FHp) and those with a negative FH (FH-). CMRglc reductions in FHm involved the same brain regions that are typically hypometabolic in clinical AD patients. Moreover, NL FHm showed significantly higher rates of CMRglc declines in AD regions as compared to FHp and FH-. Our prior work demonstrates that CMRglc reductions occur at the preclinical stages of AD and predict decline from NL cognition to AD. With all that is known about the molecular processes involved in glucose metabolism and the pathophysiology of AD, hypometabolism in NL FHm may be due to a combination of increased oxidative stress from the mitochondria and increased amyloid beta (A) deposition, which is considered by many the key pathological event in AD. The fact that mitochondrial DNA is exclusively maternally inherited in humans lends support to this hypothesis. A-related oxidative stress may play a crucial role in the initiation and progression of CMRglc abnormalities in AD, which in turn render synapses more vulnerable to neurodegeneration. The goal of this study is to examine the relationship between CMRglc, A pathology, and oxidative stress in young NL individuals at risk for AD. We propose to perform a 3-year longitudinal study of ninety-six 25-50 year old NL, divided into 4 FH groups of n=24 subjects each: FH-, FHm, FHp, maternal and paternal FH of AD (FHmp). All subjects will receive clinical, neuropsychological, blood tests, brain MRI, FDG-PET and amyloid-PET (PIB-PET) exams at baseline and follow-up. Our first aim will be to examine whether NL FHm show reduced CMRglc, increased Ass deposition and increased oxidative stress vs FH- and FHp, and whether the changes in these variables are related. Our second aim will be to examine whether FHmp show cross-sectional and longitudinal effects comparable to FHm. We will use standardized and quality controlled protocols and there is adequate power for hypothesis testing. PUBLIC HEALTH RELEVANCE: Primary prevention trials for Alzheimer's disease will require accurate identification of normal individuals at increased risk for cognitive decline. We showed that children of AD-affected mothers show reduced brain glucose metabolism in AD-vulnerable regions, which may account for the increased risk. This project will test the hypothesis that hypometabolism in children of AD-mothers is due to a combination of systemically increased oxidative stress from the mitochondria and increasing amyloid-beta deposition.